Ceftriaxone-induced encephalopathy in a patient with a normal renal function

Ceftriaxone-induced encephalopathy is an exceptionally rare adverse effect of this commonly used cephalosporin and is generally observed in patients undergoing haemodialysis or suffering from severe renal failure. We present a case of a fit woman in her mid-80s with a normal renal function who developed severe fluctuating neurological symptoms (aphasia, loss of contact, chorea-like tongue movements) while being treated with ceftriaxone for a urinary tract infection with bacteraemia. The symptoms began on day 4 of treatment and an adverse drug reaction was suspected on day 7, after exhaustive investigations failed to reveal another cause. A complete recovery was observed 3 days after discontinuing ceftriaxone. Our case highlights the need to consider the diagnosis of ceftriaxone encephalopathy, even if the traditional risk factors are lacking. In this article, we also provide a brief overview of the pathophysiology as well as a literature review concerning the subject.


BACKGROUND
Ceftriaxone-related adverse neurological effects are uncommon to very rare and mostly mild (dizziness, headache, ataxia, paresthesia). 1However, multiple case reports [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21] and a case series from a French pharmacovigilance database 22 have been published on more severe reactions, notably encephalopathy, trouble of consciousness and choreoathetosis.With ceftriaxone being one of the most commonly used parenteral antibiotics worldwide 23 , there is a possibility that many more cases of these severe adverse reactions are not readily recognised or may be confused with common delirium.The vast majority of cases involve patients with either severely impaired renal function or patients on haemodialysis.We present a case of a patient in her mid-80s with a normal renal function who developed severe encephalopathy while being treated with ceftriaxone for a urinary tract infection.

CASE PRESENTATION
A fit and autonomous female patient in her mid-80s, known for arterial hypertension, was admitted to our department for pyelonephritis with progressive asthenia and urinary symptoms.The clinical examination was unremarkable except for moderate dehydration and a fever of 39.2°C.Ceftriaxone was started at 2 g/day with a resolution of fever and urinary complaints over the next 2 days.
On day 4, the patient began presenting fluctuating and progressively worsening neurological symptoms, starting out with transitory disorientation and incomprehensible speech.On day 5, we observed fluctuating aphasia and three short episodes of loss of contact, as well as brief myoclonic movements of low amplitude in the four extremities.The symptoms reached their peak on day 7 with the aphasia periods lasting up to 1 hour, the patient gripping and not releasing objects and having chorea-like tongue movements.
On day 4 (the beginning of the neurological symptoms), the blood tests showed a normal blood glucose, a stable sodium (130 mmol/L), a slight hypophosphataemia (0.69 mmol/L), normal liver enzymes, liver function tests and coagulation panel.A bladder ultrasound revealed a urinary retention, which was catheterised.No acute postrenal kidney injury was detected.The neurological examination was non-focal, with no signs of meningitis, and the cerebral angio-CT was normal except for mild atrophy.
On day 7, in the context of persistent neurological symptoms, we obtained a lumbar puncture (normal, clear cerebrospinal fluid (CSF), 1 erythrocyte/µL, 1 leucocyte/µL, normal glucose and lactate), brain MRI (cortico subcortical atrophy with parietal predominance, no acute changes) and an electroencephalogram (EEG) (figure 1), which showed unstable background activity with superimposed diffuse fast activity (beta rhythm) and generalised discharges with triphasic morphology related to an encephalopathy.

DIFFERENTIAL DIAGNOSIS
On the day of the apparition of neurological disturbances, we excluded an acute intracranial bleed, stroke and major electrolyte perturbations and suspected a peri-infectious delirium as the cause for the symptoms.

Case report
With the apparition of aphasia and myoclonic jerks on day 5, a state of non-convulsive status epilepticus was suspected.Clonazepam (0.5 mg intravenously) was administered empirically, as a diagnostic test and a therapeutic measure, allowing for a complete resolution of symptoms for a period of about 12 hours.
On the return of symptoms on day 6 and their worsening on day 7, we searched for, and excluded, focal brain lesions, meningo-encephalitis, and epileptic disease.Despite the recent EEG, a non-convulsive status was suspected again by the on-call resident, but this time an administration of clonazepam (0.5 mg intravenously×2) improved symptoms only partially and haloperidol (0.5 mg subcutaneously) had no effect.
We did not measure serum ammonaemia in our patient with normal liver tests, no past hepatic pathology history and absence of asterixis.Rare cases of hyperammonaemia in obstructive urinary tract infections have been described 24 25 but were marked by a significant and rapid improvement in the neurological status after bladder catheterisation, 24 on the contrary to our patient whose neurological status continued to decline.

TREATMENT
Antibiotic treatment by ceftriaxone was maintained initially because of the worsening neurological condition, despite the blood and urine cultures revealing a multisensitive Escherichia coli and the favourable clinical evolution of the urinary infection the days prior.After reasonably excluding structural brain lesions, a central nervous system (CNS) infection, epileptiform activity and electrolyte perturbations, we finally attributed the clinical symptoms to ceftriaxone-induced encephalopathy on day 7.The medication was discontinued, with a switch to amoxicillin-clavulanic acid (intravenous first and per os later).

OUTCOME AND FOLLOW-UP
The aphasia symptoms disappeared on day 9 and complete recovery was noted on day 10, 3 days after stopping ceftriaxone.Afterwards, the patient signalled vaguely remembering being asked questions by the staff, but not being able to produce responses.She was discharged home on day 19.A phone call 3 months later confirmed the absence of neurological symptoms or any other general complaints.
The authors of the French pharmacovigilance database paper found 152 serious reports, with the declared patients presenting mostly with encephalopathy (20.8% of the adverse reactions), confused state (15.7%) and convulsions (13%). 22The median onset time was 4 days and the median duration of symptoms was 4.5 days. 22Most of the patients were over 65 years old (69.7%) and had renal impairment (74.6%). 22The analysis of the Japanese Adverse Drug Event Report database suggested that ceftriaxone might be associated with encephalopathy, and the risk might be increased in patients who have CKD, are receiving ceftriaxone at a dosage of >2 g/day, are treated for more than 14 days or are females. 28able 1 summarises the case reports and the case series.Out of the total 27 patients, 74.1% were 65 years of age or older, 59.3% were females and only 2 (7.4%) had a normal renal function.The median time to onset was 5 days (minimum 2 days, maximum 23 days) and the median time to resolution was 3 days (minimum 1 day, maximum 12 days).

Case report
Please note that we decided to exclude one case report because of possible confounding factors not detailed in the report 26 and one case series because of radically different patient descriptions in the written text and the supplied chart. 270][31] From a pharmacokinetic point of view, the metabolism of ceftriaxone is negligible and it is eliminated renally (55% of the drug) and through the biliary pathway (45%).In patients with mild to moderate renal impairment, changes in the regular dosage regimens are not required, provided liver function is not impaired.In cases of creatinine clearance less than 10 mL/min periodic monitoring of serum ceftriaxone concentrations is recommended, especially if combined with hepatic insufficiency. 1 A prolonged half-life of elimination is observed in older patients (7.3±1.6 hours in patients aged 18-49 years, 8.3±2.2 hours in patients aged 50-74 years and 14.2±2.9hours in patients aged 75-92 years). 1 The age-associated changes in half-life appear to result from changes in systemic clearance since the renal and hepatic functions were normal in all these patients. 1Also, the pharmacokinetics of total plasma ceftriaxone are non-linear: the drug is known for a saturable plasma protein binding within the therapeutic range of up to 200 µg/mL with stable free fraction levels at 5%-10% and significantly higher levels of the free drug in supratherapeutic doses (free fraction at 42% at a plasma level of 653 µg/mL). 1 In the case of CNS effects, the free portion of the drug is the most important to consider, seeing as in the presence of an intact blood-brain barrier, the binding proteins, in particular albumin and globulins, pass the barrier only to a small degree. 17 32 33he clinical presentation is not specific and can be easily mistaken for delirium, with most patients being drowsy, having a decreased level of consciousness or agitation.While aimlessly picking at objects and plucking at the air can be associated with delirium 34 , the astute clinician can pick up on chorea-like movements or myoclonic jerks more compatible with encephalopathy.
The diagnosis is mostly one of exclusion, with most reports mentioning a search for electrolyte abnormalities, brain imaging and often a lumbar puncture in a search for secondary causes.The EEG might reveal diffuse slow waves, generalised periodic discharges with triphasic morphology or, in rarer and more severe cases, signs of non-convulsive status epilepticus.Serum and CSF ceftriaxone dosing can also be a helpful diagnostic modality.The normal serum trough level in healthy volunteers receiving 2 g/24 hours has been shown to be 13-15 µg/mL 35 and the maximum CSF levels after a single 2 g dose in patients with non-inflamed meninges are reported to be 0.18-1.04µg/mL. 36n the reviewed literature, in patients presenting with severe neurological symptoms, the levels were significantly higher than the normal range when measured, with plasma levels varying between 27.9 and 472 µg/mL 10 13 16-19 21 and the CSF levels being in the range of 5.9-27.9µg/mL. 13 17-19 21he basis of treatment is discontinuing ceftriaxone.Benzodiazepines might be helpful for transient symptom control or in the case of non-convulsive status epilepticus. 2 3While ceftriaxone is not removed through haemodialysis 1 , haemoperfusion might hasten elimination and therefore recovery. 19In affected patients ceftriaxone readministration should be avoided as it can lead to a new onset of encephalopathy. 3aving reviewed the basic pharmacology and available literature, we can assume that the risk factors for developing a ceftriaxone-induced encephalopathy are older age (especially over 75 years old), higher dosing, severely impaired renal or hepatic functions (especially if combined) and undernourishment or decompensated cirrhosis (low binding protein levels leading to a higher fraction of free ceftriaxone).
Our case is notable because of the absence of these factors, except for age.It is of note that the only other published detailed case report of an adult patient having ceftriaxoneinduced encephalopathy and normal renal function consists of an 80-year-old woman, receiving a higher than usual ceftriaxone dose for pneumonia (2.5 g/day), who also had a subacute head injury with cerebral contusions. 14ur case shows that ceftriaxone-induced encephalopathy should be considered as a differential diagnosis of impaired mental status, even in patients without renal failure.
Looking back at our patient with hindsight, we can also observe how an anchoring bias on parainfectious delirium led to continued ceftriaxone administration, a late consideration of a drug-induced encephalopathy in the context of absent risk factors and a prolonged hospitalisation because of secondary drug effects.

Learning points
► Ceftriaxone encephalopathy is rare, possibly underrecognised, and occurs mostly in older patients with severe renal impairment.► The diagnosis is mostly clinical and made after the exclusion of other probable causes.► Atypical movements, ceftriaxone dosing and EEG can help orientate the clinician, but the key is to consider the diagnosis, even if the risk factors are lacking.
Acknowledgements The authors would like to thank Dr Pharm.Beney Johnny for his valuable insights during the writing of the manuscript, as well as the patient who graciously consented to having her case published.

Contributors
The following authors were responsible for drafting of the text, sourcing and editing of clinical images, investigation results, drawing original diagrams and algorithms, and critical revision for important intellectual content: AZ, VA and BR.The following authors gave final approval of the manuscript: AZ, VA and BR.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Consent obtained directly from patient(s).
Provenance and peer review Not commissioned; externally peer reviewed.

Open access
This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made.See: https://creativecommons.org/ licenses/by/4.0/.
Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research.They should not be used in isolation to guide treatment choices or public health policy.

Figure 1
Figure 1 EEG showing an unstable background activity with superimposed diffuse fast activity (beta rhythm).Arrows show examples of generalised discharges with triphasic morphology.Recorded according 10-20 system, high pass filter set at 1 Hz, low-pass filter set at 70 Hz, notch filter set at 50 Hz.Display with a bipolar longitudinal montage, 10 s/pages and 70 µV/cm.EEG, electroencephalogram.